Metabolic disorders, such as lipid storage disease and glycogen storage disease, can have devastating effects on patients. The Lipid storage diseases represent a group of disorders in which harmful amounts of lipids accumulate in various cells and tissues in the body. Glycogen storage disease is the result of defects in the processing of glycogen synthesis or breakdown within cells. Individuals with lipid/glycogen storage disorders either do not produce enough of one of the enzymes needed to break down (metabolize) lipids, or glycogen, or they produce enzymes that do not work properly. Over time, this excessive storage of fats and glycogen can cause permanent cellular and tissue damage, for example, in the heart, muscle, brain, peripheral nervous system, liver, spleen, and bone marrow.
Neutral lipid storage disease myopathy subtype (NLSD-M) is caused by loss-of-function mutations in PNPLA2, which encodes adipose triglyceride lipase (ATGL, also known as desnutrin) (Fischer et al., 2007). ATGL is expressed in a variety of tissues, including cardiac and skeletal muscle (Lake et al., 2005; Pinent et al., 2008), and as it cleaves the first ester bond in triacylglycerol (TAG), it is the rate-limiting enzyme in the breakdown of intracellular TAG droplets to provide free fatty acid for cellular energy metabolism (Haemmerle et al., 2006). Consistent with this function, the dominant phenotype of NLSD-M is excessive intracellular TAG accumulation in multiple tissues, notably in cardiac and skeletal muscle, which then go on to develop myopathy (Fischer et al. 2007; Kobayashi, K. et al., 2008). ATGL-knockout (ATGL-KO) mice exhibit an NLSD-M-like phenotype and suffer from fatal cardiac myopathy secondary to massive fat accumulation in the heart (Haemmerle et al., 2006).
Currently there is a lack of specific treatments available for most of the lipid/glycogen storage disorders and restricting one's diet does not prevent lipid/glycogen buildup in cells and tissues. Enzyme replacement therapy is available for some, e.g. patients with type 1 and type 3 Gaucher disease. However, most available treatments for storage disorders are preventative of secondary symptoms. For example, individuals having lipid storage disease associated with anemia may require blood transfusions and, in some patients, an enlarged spleen must be removed to improve cardiopulmonary function. For patients with Fabry disease, the drugs phenyloin and carbamazepine may be prescribed to help treat pain (including bone pain).
Given the lack of specific therapies for lipid/glycogen storage diseases, there is need in the art for compositions and methods for treatment of these disorders.